Drug Discovery programme: understanding the potential
From the Winter 2015 issue of Care and cure magazine, find out about our Drug Discovery programme that reuses existing drugs to fight dementia.
Developing a new drug can take 10 to 15 years and cost up to a billion pounds. Even after that, there is still no guarantee that the drug will work and be approved for use. One promising approach to make this process cheaper and faster is to test existing drugs to see if they have the potential to treat an entirely different disease.
In 1988, Nobel Prize winner James Black said, 'The most fruitful basis for the discovery of a new drug is to start with an old drug.' Despite huge technological advances since then, his words remain relevant today. In recent years, researchers have not only drawn inspiration from old drugs, but are increasingly taking them wholesale and testing them against other diseases.
In 2012, an Alzheimer's Society research review highlighted five existing drugs that might be suitable for testing against dementia. This was the start of the Society's Drug Discovery Programme, which has focused on 'repurposing' drugs for dementia. Since the review was published all five of the drugs listed have been tested or are currently in trials.
The advantage of studying existing drugs is that we already understand how they behave in the body and what the side-effects are. Often they may also be cheaper to buy. This is a promising approach that is also being used for other conditions such as multiple sclerosis and breast cancer.
Improving blood flow
One drug that is currently being tested is tadalafil, a treatment for erectile dysfunction. Dr Atticus Hainsworth and his team at St George's Hospital are investigating whether tadalafil might also help people with vascular dementia. There are currently no treatments for vascular dementia, which is caused when the blood supply to the brain is impaired. It is the second most common cause of dementia, affecting 150,000 people across the UK.
The study is testing whether tadalafil improves the blood supply to deep regions of the brain in people with small vessel disease – the main cause of vascular dementia in older people.
'These are people who do not have dementia, although they will be at risk of developing it later, by virtue of having already had some vascular disease in their brain, so people who have had small strokes. From the MRI scan we can see that there is a certain amount of damage already, so they’ve got the pathological process, that’s how we know we've got the right people,' says Dr Jeremy Isaacs, Consultant Neurologist and Principal Investigator of the study.
'The reason the brain cells get damaged in vascular disease is to do with changes in blood supply – small blood vessels are becoming more rigid and narrow,' adds Dr Hainsworth, who is a Senior Lecturer in Cerebrovascular Disease. 'If we could open up these blood vessels and get more blood through them, that could help.'
One step at a time
The tadalafil study is at the 'proof of concept' stage, which aims to show that the drug does have a biologically relevant effect. 'We're particularly interested in what it does in the arteries in the brain,' says Dr Hainsworth. 'The next step is to ask does it have some effect on brain function itself. Two years from now, we may be back asking for funding to do the bigger trial – the real efficacy trial that would tell us about improved cognition.'
Often the idea to test existing drugs comes after research into the fundamental biology of the disease reveals a new potential target for treatment. If there's already a drug available that has been designed to treat that target, then it could cut out much of the process for developing a new drug and testing its safety.
This was the case for the tadalafil study, which came about when earlier research conducted by Dr Hainsworth and colleagues found that the target for tadalafil (an enzyme called PDE5) is present in brain arteries. This led to the idea that vasodilator drugs, which increase blood flow, might be beneficial to people who have small vessel disease.
Repurposing drugs is nothing new; in fact tadalafil is closely related to one of the most famous repurposed drugs – Viagra. That was originally developed to treat high blood pressure but researchers noted that it had an unexpected, and highly profitable, side-effect.
Even some of the current treatments for Alzheimer's disease are repurposed drugs. Memantine was originally developed in 1968 to treat flu and galantamine was discovered in the 1950s and has been used in anaesthesia and the treatment of nerve pain.
The repurposing of drugs is going through a renaissance as researchers investigating a number of diseases try to make the most of what is already available. An annual conference dedicated to drug repurposing is now in its fifth year, drawing in experts from around the world. Earlier this year a multiple sclerosis trial began testing drugs originally developed for heart disease, depression and motor neurone disease.
Similarly, a wide range of drugs is being investigated in dementia research. There are currently studies into drugs for arthritis, diabetes, blood pressure and even anantibiotic. These drugs would not be able to treat the root cause of the dementia, but instead might be able to treat some of the changes that happen in the brain, such as inflammation, blood flow or insulin resistance. This could help to reduce the stress on brain cells and hopefully slow the progression of dementia or even delay its onset, if caught early enough.
Although it is still early days for tadalafil, Dr Hainsworth can see its potential. 'For me, a success would be a drug on the shelves - in the clinic, that we could give to patients. Either when they've got a diagnosis but more likely in a prevention strategy if you find you have risk factors. If you could say to someone in their sixties, "I'm afraid you're going to have to take this pill every morning and it will cut your risk of dementia," I think they'd probably do it.'